This invention relates to a novel synthesis for the preparation of 3-amino-2-methylbenzotrifluoride. More particularly, this invention relates to a novel process wherein 3-amino-2-methylbenzotrifluoride is prepared from relatively inexpensive and readily available reactants under conditions which are essentially non-hazardous.
The compound 3-amino-2-methylbenzotrifluoride, is a valuable intermediate in the preparation of therapeutic agents. For example, U.S. Pat. No. 3,337,750 discloses that 2(2-methyl-3-trifluoromethyl)anilino nicotinic acid is a useful therapeutic agent having valuable anti-inflammatory/analgesic properties. U.S. Pat. No. 3,390,172 discloses that N-(2-methyl-3-trifluoromethylphenyl)anthranilic acid is a valuable anti-inflammatory agent. In both instances, 3-amino-2-methylbenzotrifluoride is a essential intermediate in preparing the final therapeutic agent.
In U.S. Pat. No. 3,390,170, 3-amino-2-methylbenzotrifluoride is prepared by treating 2-methyl-2-nitrobenzoic acid with sulfur tetrafluoride at temperatures in excess of 100.degree. C. in a stainless steel bomb for about 15 hours under higher pressure to produce 3-nitro-2-methyl-benzotrifluoride. The latter nitro compound is chemically reduced to 3-amino-2-methylbenzotrifluoride. This process presents a safety hazard in that the high pressure conditions could cause the reaction vessel to rupture, thereby releasing the corrosive reaction mixture.
U.S. Pat. No. 4,209,464 discloses a process for preparing 3-amino-2-methylbenzotrifluoride comprising (a) condensing a 3-amino-4-X-benzotrifluoride with dimethylsulfoxide in the presence of an activating agent, (b) heating the N-(2-X-5-trifluoromethylphenyl)-S,S-dimethyl sulfimide at from about 85.degree. C. to about 200.degree. C., and (c) chemically reducing the so-formed 3-amino-2-methylthiomethylbenzotrifluoride wherein X is hydrogen, chloro, bromo, iodo or alkylthio.
We have now discovered a method for preparing 3-amino-2-methylbenzotrifluoride which utilizes relatively inexpensive and readily available starting materials and which affords the desired product in good yield.
More specifically, this invention is the process for preparing 3-amino-2-methylbenzotrifluoride which comprises: (a) nitrating benzotrifluoride to prepare 3-nitrobenzotrifluoride, (b) reacting the latter compound with trimethyl sulphoxonium halide to afford 3-nitro-2-methylbenzotrifluoride and (c) reducing the nitro substituted compound to 3-amino-2-methylbenzotrifluoride.
The foregoing process may be depicted as follows: ##STR1##
The nitration step (a) may be effected by using various nitrating agents such as concentrated nitric-sulfuric acid, potassium nitrate--sulfuric acid and nitric acid-acetic acid. The preferred nitrating agent is connected nitric-sulfuric acid. The reaction is carried out by slowly adding fuming nitric acid to a mixture of benzotrifluoride in concentrated sulfuric acid while maintaining the temperature of the reaction between 0.degree. to 40.degree. C., preferably 20.degree.-30.degree. C. When the addition is complete, the reaction is allowed to continue for 1 to 2 hours, preferably 1 hour at room temperature. 3-Nitrobenzotrifluoride is isolated from the reaction mixture by conventional techniques.
Methylation of 3-nitrobenzotrifluoride is carried out by reacting said compound with dimethyloxosulfonium methylide in a suitable aprotic solvent, e.g. dimethylsulfoxide, tetrahydrofuran and the like. The dimethyloxosulphonium methylide is derived from trimethyl sulphoxonium halide, e.g. the chloride or iodide, and a suitable base such as sodium hydride, sodium hydroxide or potassium hydroxide. The methylation reaction is carried out in an inert atmosphere, such as nitrogen, argon and the like. The reaction is carried out at a temperature below 30.degree. C. and preferably at a temperature of about 20.degree. C. Isolation of the desired compound is by conventional techniques.
The nitro group of 3-nitro-2-methylbenzotrifluoride is then reduced to an amino group by conventional methods well known to persons skilled in the art. In the preferred method, the nitro group is reduced by catalytic hydrogenation. Suitable catalysts include palladium on conton, or other platinum metals, and the like. Such methods are known to those skilled in the art and are described in G. W. Roberts, "Catalysis in Organic Synthesis", Academic Press, N.Y., 1976; P. H. Emmett and M. C. Yao, J.A.C.S., 81, 4125 (1959); N. Kornblum and A. Fishbein, J.A.C.S., 77, 6266 (1955); and G. B. Patent No. 832,153. The hydrogenation can be carried out by dissolving the nitro compound in an appropriate solvent such as methanol, ethanol, isopropanol and the like, in an inert atmosphere such as nitrogen, argon and the like, at room temperature. Hydrogen is passed into the solution at a temperature of from 40.degree. C., preferably 40.degree.-45.degree. C. The pressure utilized during the hydrogenation is not critical, however, it is convenient to conduct the reaction at atmosphereic pressure. The reaction is run to completion which can be determined by thin-layer chromatography. The final product is isolated by conventional techniques such as filtration, distillation, etc.